tbuckley/cabot-search huggingface dataset:
Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children
Authors: Eran Mick, Alexandra Tsitsiklis, Jack Kamm, Katrina L. Kalantar, Saharai Caldera, Amy Lyden, Michelle Tan, Angela M. Detweiler, Norma Neff, Christina M. Osborne, Kayla M. Williamson, Victoria Soesanto, Matthew Leroue, Aline B. Maddux, Eric A.F. Simões, Todd C. Carpenter, Brandie D. Wagner, Joseph L. DeRisi, Lilliam Ambroggio, Peter M. Mourani, Charles R. Langelier
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDLower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI. Whether it can be applied at scale and in a pediatric population to enable improved diagnosis and treatment remains unclear.METHODSWe used tracheal aspirate RNA-Seq to profile host gene expression and respiratory microbiota in 261 children with acute respiratory failure. We developed a gene expression classifier for LRTI by training on patients with an established diagnosis of LRTI (n = 117) or of noninfectious respiratory failure (n = 50). We then developed a classifier that integrates the host LRTI probability, abundance of respiratory viruses, and dominance in the lung microbiome of bacteria/fungi considered pathogenic by a rules-based algorithm.RESULTSThe host classifier achieved a median AUC of 0.967 by cross-validation, driven by activation markers of T cells, alveolar macrophages, and the interferon response. The integrated classifier achieved a median AUC of 0.986 and increased the confidence of patient classifications. When applied to patients with an uncertain diagnosis (n = 94), the integrated classifier indicated LRTI in 52% of cases and nominated likely causal pathogens in 98% of those.CONCLUSIONLower airway metagenomics enables accurate LRTI diagnosis and pathogen identification in a heterogeneous cohort of critically ill children through integration of host, pathogen, and microbiome features.FUNDINGSupport for this study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (UG1HD083171, 1R01HL124103, UG1HD049983, UG01HD049934, UG1HD083170, UG1HD050096, UG1HD63108, UG1HD083116, UG1HD083166, UG1HD049981, K23HL138461, and 5R01HL155418) as well as by the Chan Zuckerberg Biohub.
Cancer-associated fibroblast-secreted glucosamine alters the androgen biosynthesis program in prostate cancer via HSD3B1 upregulation
Authors: Di Cui, Jianneng Li, Ziqi Zhu, Michael Berk, Aimalie Hardaway, Jeffrey McManus, Yoon-Mi Chung, Mohammad Alyamani, Shelley Valle, Ritika Tiwari, Bangmin Han, Maryam Goudarzi, Belinda Willard, Nima Sharifi
Journal: Journal of Clinical Investigation (2023)

After androgen deprivation, prostate cancer frequently becomes castration resistant (CRPC), with intratumoral androgen production from extragonadal precursors that activate the androgen receptor pathway. 3β-Hydroxysteroid dehydrogenase-1 (3βHSD1) is the rate-limiting enzyme for extragonadal androgen synthesis, which together lead to CRPC. Here, we show that cancer-associated fibroblasts (CAFs) increased epithelial 3βHSD1 expression, induced androgen synthesis, activated the androgen receptor, and induced CRPC. Unbiased metabolomics revealed that CAF-secreted glucosamine specifically induced 3βHSD1. CAFs induced higher GlcNAcylation in cancer cells and elevated expression of the transcription factor Elk1, which induced higher 3βHSD1 expression and activity. Elk1 genetic ablation in cancer epithelial cells suppressed CAF-induced androgen biosynthesis in vivo. In patient samples, multiplex fluorescent imaging showed that tumor cells expressed more 3βHSD1 and Elk1 in CAF-enriched areas compared with CAF-deficient areas. Our findings suggest that CAF-secreted glucosamine increases GlcNAcylation in prostate cancer cells, promoting Elk1-induced HSD3B1 transcription, which upregulates de novo intratumoral androgen synthesis to overcome castration.
Evidence for involvement of tumor necrosis factor‐α in apoptotic death of bone marrow cells in myelodysplastic syndromes
Authors: Suneel D. Mundle, Ambereen Ali, Jonathan D. Cartlidge, Samina Reza, Sairah Alvi, Margaret M. Showel, B. Yifwayimare Mativi, Vilasini T. Shetty, Parameswaran Venugopal, Stephanie A. Gregory, Azra Raza
Journal: American Journal of Hematology (1999)
T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers
Authors: Kristen E. Schratz, Diane A. Flasch, Christine C. Atik, Zoe L. Cosner, Amanda L. Blackford, Wentao Yang, Dustin L. Gable, Paz J. Vellanki, Zhimin Xiang, Valeriya Gaysinskaya, Robert H. Vonderheide, Lisa M. Rooper, Jinghui Zhang, Mary Armanios
Journal: Cancer Cell (2023)

Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients' predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves.
Glucose intolerance in pregnancy and risk of early-onset type 2 diabetes: a population-based cohort study
Authors: Aya Bardugo, Cole D Bendor, Ran Shmuel Rotem, Avishai M Tsur, Estela Derazne, Hertzel C Gerstein, Dorit Tzur, Orit Pinhas-Hamiel, Tali Cukierman-Yaffe, Itamar Raz, Moshe Hod, Amir Tirosh, Yael Lebenthal, Arnon Afek, Gabriel Chodick, Gilad Twig
Journal: The Lancet Diabetes & Endocrinology (2023)
Structured, multicomponent, community-based programme for women's health and infant health and development in rural Vietnam: a parallel-group cluster randomised controlled trial
Authors: Jane Fisher, Thach Tran, Ha Tran, Stanley Luchters, David B Hipgrave, Hau Nguyen, Thuy Tran, Sarah Hanieh, Julie Anne Simpson, Beverley-Ann Biggs, Tuan Tran
Journal: The Lancet Child & Adolescent Health (2023)
Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial
Authors: Christopher Melani, Kennichi Dowdell, Stefania Pittaluga, Kieron Dunleavy, Mark Roschewski, Joo Y Song, Sara Calattini, Jun-ichi Kawada, David A Price, Pratip K Chattopadhyay, Mario Roederer, Andrea N Lucas, Seth M Steinberg, Elaine S Jaffe, Jeffrey I Cohen, Wyndham H Wilson
Journal: The Lancet Haematology (2023)
The effect of monthly vitamin D supplementation on fractures: a tertiary outcome from the population-based, double-blind, randomised, placebo-controlled D-Health trial
Authors: Mary Waterhouse, Peter R Ebeling, Donald S A McLeod, Dallas English, Briony Duarte Romero, Catherine Baxter, Bruce K Armstrong, Gunter Hartel, Michael Kimlin, Rachel L O'Connell, Jolieke C van der Pols, Alison J Venn, Penelope M Webb, David C Whiteman, Rachel E Neale
Journal: The Lancet Diabetes & Endocrinology (2023)
Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study
Authors: Toni K Choueiri, David F McDermott, Jaime Merchan, Todd M Bauer, Robert Figlin, Elisabeth I Heath, M Dror Michaelson, Edward Arrowsmith, Anishka D'Souza, Song Zhao, Ananya Roy, Rodolfo Perini, Donna Vickery, Scott S Tykodi
Journal: The Lancet Oncology (2023)
Effects of a Responsive Parenting Intervention Among Black Families on Infant Sleep
Authors: Justin A. Lavner, Emily E. Hohman, Steven R. H. Beach, Brian K. Stansfield, Jennifer S. Savage
Journal: JAMA Network Open (2023)

Importance Black individuals in the US experience sleep disparities beginning in infancy and continuing throughout the lifespan, suggesting early interventions are needed to improve sleep. Objective To investigate whether a responsive parenting (RP) intervention for Black mothers improves infant sleep and increases responsive sleep parenting practices. Design, Setting, and Participants This is a post hoc secondary analysis of the Sleep SAAF (Strong African American Families) study, a randomized clinical trial comparing an RP intervention with a safety control condition over the first 16 weeks post partum. Data were collected between spring 2018 and summer 2021. Families were recruited from the mother-infant nursery at Augusta University Medical Center, Augusta, Georgia, and completed home visits at 1, 3, 8, and 16 weeks post partum. Primiparous Black mother-infant dyads were screened for eligibility using medical records. Results were analyzed on an intention-to-treat model. Data were analyzed from March 2022 to January 2023. Interventions The RP intervention curriculum focused on infant sleep, soothing and crying, and feeding. The control group received a safety intervention. Community research associates delivered the interventions during home visits at 3 and 8 weeks post partum. Main Outcomes and Measures The primary end point was infant sleep duration at 16 weeks. Mothers reported on bedtime routine and sleep behaviors, infant sleep duration, and nighttime waking and feeding at 8 and 16 weeks post partum using questionnaires. Results A total of 212 Black mothers (mean [SD] age, 22.7 [4.5] years) were randomized, including 208 mothers (98.6%) who identified as non-Hispanic and 3 mothers (1.4%) who identified as Hispanic; 108 mothers were randomized to the RP group and 104 mothers were randomized to the control group. At 16 weeks post partum, infants in the RP group had longer reported nighttime sleep duration (mean difference, 40 [95% CI, 3 to 77] minutes), longer total sleep duration (mean difference, 73 [95% CI, 14 to 131] minutes), fewer nighttime wakings (mean difference, −0.4 [95% CI, −0.6 to −0.1] wakings), and greater likelihood of meeting guidelines of at least 12 hours of total sleep per day (risk ratio [RR], 1.4 [95% CI, 95% CI, 1.1 to 1.8]) than controls. Relative to controls, mothers in the RP group more frequently reported engaging in some RP practices, including giving the baby a few minutes to fall back asleep on their own (RR, 1.6 [95% CI, 1.0 to 2.6]) and being less likely to feed their baby as the last activity before bed (RR, 0.5 [95% CI, 0.3 to 0.8]). Conclusions and Relevance This secondary analysis of a randomized clinical trial found that an RP intervention for Black families improved infant sleep and increased some responsive sleep parenting practices. Trial Registration ClinicalTrials.gov Identifier: NCT03505203
Incremental Health Care Costs of Self-Reported Functional Impairments and Phenotypic Frailty in Community-Dwelling Older Adults
Authors: Kristine E. Ensrud, John T. Schousboe, Allyson M. Kats, Brent C. Taylor, Cynthia M. Boyd, Lisa Langsetmo
Journal: Annals of Internal Medicine (2023)

Background: Health care systems need better strategies to identify older adults at risk for costly care to select target populations for interventions to reduce health care burden. Objective: To determine whether self-reported functional impairments and phenotypic frailty are associated with incremental health care costs after accounting for claims-based predictors. Design: Prospective cohort study. Setting: Index examinations (2002 to 2011) of 4 prospective cohort studies linked with Medicare claims. Participants: 8165 community-dwelling fee-for-service beneficiaries (4318 women, 3847 men). Measurements: Weighted (Centers for Medicare & Medicaid Services Hierarchical Condition Category index) and unweighted (count of conditions) multimorbidity and frailty indicators derived from claims. Self-reported functional impairments (difficulty performing 4 activities of daily living) and frailty phenotype (operationalized using 5 components) derived from cohort data. Health care costs ascertained for 36 months after index examinations. Results: Average annualized costs (2020 U.S. dollars) were $13 906 among women and $14 598 among men. After accounting for claims-based indicators, average incremental costs of functional impairments versus no impairment in women (men) were $3328 ($2354) for 1 impairment increasing to $7330 ($11 760) for 4 impairments; average incremental costs of phenotypic frailty versus robust in women (men) were $8532 ($6172). Mean predicted costs adjusted for claims-based indicators in women (men) varied by both functional impairments and the frailty phenotype ranging from $8124 ($11 831) among robust persons without impairments to $18 792 ($24 713) among frail persons with 4 impairments. Compared with the model with claims-derived indicators alone, this model resulted in more accurate cost prediction for persons with multiple impairments or phenotypic frailty. Limitation: Cost data limited to participants enrolled in the Medicare fee-for-service program. Conclusion: Self-reported functional impairments and phenotypic frailty are associated with higher subsequent health care expenditures in community-dwelling beneficiaries after accounting for several claims-based indicators of costs. Primary Funding Source: National Institutes of Health.
Hippocampal spatio-predictive cognitive maps adaptively guide reward generalization
Authors: Mona M. Garvert, Tankred Saanum, Eric Schulz, Nicolas W. Schuck, Christian F. Doeller
Journal: Nature Neuroscience (2023)

The brain forms cognitive maps of relational knowledge-an organizing principle thought to underlie our ability to generalize and make inferences. However, how can a relevant map be selected in situations where a stimulus is embedded in multiple relational structures? Here, we find that both spatial and predictive cognitive maps influence generalization in a choice task, where spatial location determines reward magnitude. Mirroring behavior, the hippocampus not only builds a map of spatial relationships but also encodes the experienced transition structure. As the task progresses, participants' choices become more influenced by spatial relationships, reflected in a strengthening of the spatial map and a weakening of the predictive map. This change is driven by orbitofrontal cortex, which represents the degree to which an outcome is consistent with the spatial rather than the predictive map and updates hippocampal representations accordingly. Taken together, this demonstrates how hippocampal cognitive maps are used and updated flexibly for inference.
Comparison of Genetic Profiles of Neonates in Intensive Care Units Conceived With or Without Assisted Reproductive Technology
Authors: Zhongwen Huang, Feifan Xiao, Hui Xiao, Yulan Lu, Lin Yang, Deyi Zhuang, Liping Chen, Qiufen Wei, Yinmo Jiang, Gang Li, Bingbing Wu, Zhiwei Liu, Wenhao Zhou, Huijun Wang
Journal: JAMA Network Open (2023)

Importance A growing number of children are conceived with assisted reproductive technology (ART). However, there is a lack of studies systematically analyzing the genetic landscape of live-born children conceived through ART who need intensive care in the neonatal period. Objective To investigate the incidence and type of molecular defects among neonates conceived through ART who are in intensive care units (NICUs) with suspected genetic conditions. Design, Setting, and Participants This was a cross-sectional study using data from the China Neonatal Genomes Project, a multicenter national neonatal genome data set managed by the Children’s Hospital of Fudan University. All participants were from level III and IV NICUs and included 535 neonates conceived through ART with suspected genetic conditions, with data collected between August 1, 2016, and December 31, 2021, and 1316 naturally conceived neonates with suspected genetic conditions in the same clinical settings, with data collected between August 1, 2016, and December 31, 2018. The data were analyzed between September 2021 and January 2023. Exposures Whole-exome sequencing or target clinical exome sequencing with pathogenic or likely pathogenic single-nucleotide variant (SNV) and copy number variation (CNV) detection was performed for each individual. Main Outcomes and Measures The primary outcome was the molecular diagnostic yield, mode of inheritance, spectrum of genetic events, and incidence of de novo variants. Results A total of 535 neonates conceived through ART (319 boys [59.6%]) and 1316 naturally conceived neonates (772 boys [58.7%]) were included. A genetic diagnosis was established for 54 patients conceived through ART (10.1%), including 34 patients with SNVs (63.0%) and 20 with CNVs (37.0%). In the non-ART group, 174 patients (13.2%) received a genetic diagnosis, including 120 patients with SNVs (69.0%) and 54 with CNVs (31.0%). The overall diagnostic yield was comparable between the ART group and the naturally conceived neonates (10.1% vs 13.2%; odds ratio [OR], 0.74; 95% CI, 0.53-1.02), as was the proportion of SNVs (63.0% vs 69.0%; OR, 0.68; 95% CI, 0.46-1.00) and CNVs (37.0% vs 31.0%; OR, 0.91; 95% CI, 0.54-1.53) detected by sequencing. Furthermore, the proportions of de novo variants in the ART group and the non-ART group were similar (75.9% [41 of 54] vs 64.4% [112 of 174]; OR, 0.89; 95% CI, 0.62-1.30). Conclusions and Relevance This cross-sectional study of neonates in NICUs suggests that the overall genetic diagnostic yield and the incidence of de novo variants were similar between live-born neonates conceived through ART and naturally conceived neonates in the same settings.
Facilitating Shared Decision Making Among Black Patients at Risk for Sudden Cardiac Arrest
Authors: Kevin L. Thomas, Sana M. Al-Khatib, Andrzej S. Kosinski, Samuel F. Sears, Nancy M. Allen LaPointe, Larry R. Jackson, Daniel D. Matlock, Daniel Haithcock, B. Judson Colley, David S. Hirsh, Eric D. Peterson
Journal: Annals of Internal Medicine (2023)

Racial disparities in implantable cardioverter-defibrillator (ICD) implantation are multifactorial and are partly explained by higher refusal rates.
MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner
Authors: Guojia Xie, Ji-Eun Lee, Anna D. Senft, Young-Kwon Park, Younghoon Jang, Shreeta Chakraborty, Joyce J. Thompson, Kaitlin McKernan, Chengyu Liu, Todd S. Macfarlan, Pedro P. Rocha, Weiqun Peng, Kai Ge
Journal: Nature Genetics (2023)
Measure for Measure: Condemning the Actor and Not the Fault
Authors: Elizabeth G. Epstein, Ashley R. Hurst, Dawn Bourne, Mary Faith Marshall
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Moral Distress: What Are We Measuring? DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Medicare Advantage vs Traditional Medicare and 30-Day Mortality in Patients With AMI
Authors: Eric Roehm
Journal: JAMA (2023)

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Assessment of First-line Therapy With Midazolam for Prehospital Seizures in Children
Authors: Danielle Shavit, Refael Strugo, Maya Siman-Tov, Shira Nov, Itai Shavit
Journal: JAMA Network Open (2023)

This cohort study assesses the effectiveness of midazolam treatment in terminating pediatric seizures in the prehospital setting.
Historicizing Technological Hegemony
Authors: Joel D. Howell
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Materialized Oppression in Medical Tools and Technologies DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.